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HIV susceptibility locus protects against an extinct virus

The TRIM5α protein in humans doesn't resist HIV very well but may have once protected us from another ape virus.

7 min read

What's behind the headline about "resurrecting an ancient virus"?

The study, which appears tomorrow in Science, focuses on Pan troglodytes endogenous retrovirus (PtERV1). More than 100 copies of inactive PtERV1 are sprinkled throughout the chimpanzee and gorilla genomes, whereas humans have none. "About 4 million years ago, this virus was active and independently infecting all these species, but not humans," says virologist Michael Emerman, who conducted the study with evolutionary biologist Harmit Malik and postgraduate student Shari Kaiser, all of whom work at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

That's a pretty radical genome-wide difference between humans and the African apes. It's interesting that the chimpanzee and gorilla lineages were capable of exchanging viruses from early in their evolution. If they are right about the 4 Ma age, that is about halfway between the common ancestor of chimpanzees and gorillas (around 7--10 Ma) and today. Since they still exchange viruses today (including Ebola), you might think that it wouldn't be surprising that they did so in the Pliocene. But I think it's important because it establishes sympatry of the two apes: the ancestors of today's chimpanzees and gorillas lived in the same geographic region. If the two lineages originated in an allopatric speciation, then they had expanded their ranges by the Pliocene to overlap with each other. And sympatry means that they must have been adaptively differentiated by that time.

The now-extinct virus was interesting to this research group for another reason: apparently, a protein essential to HIV resistance in other primates lets humans down by being resistant to the extinct virus. This is a pretty tricky storyline, so I'll try to explain. The protein is named TRIM5α, it is key to the immune response to viruses. The human form of the protein does not do a good job of fighting HIV, and some other primates have a form that resists HIV infection must more effectively. So this protein has been a focus of HIV research.

When Kaiser and colleagues examined the sequences of the ancient retrovirus imprisoned in the chimpanzee genome, they found that one of the virus' genes interacts with TRIM5α. Prior work had established the variation among primates in TRIM5α's response to HIV. Now, they found that no known primate TRIM5α sequence provides an effective response to both HIV and the ancient chimpanzee virus.

In other words, this ancient chimpanzee virus, PtERV1, is like the immune system equivalent of Bizarro Superman -- it's just the opposite of the real thing.

In terms of hominid evolution, there is the obvious question of why humans never acquired the many endogenous copies of this viral genome. Clearly, ancient hominids did not have the virus in substantial enough numbers to result in its incorporation into our genome. But why not? In particular, did our TRIM5α sequence protect us?

Here's what Kaiser and colleagues have to say:

Although we cannot rule out the possibility that PtERV1 never infected human ancestors for other reasons (SOM Text, note 1), our data do suggest the possibility that TRIM5 was fixed in human populations because of its ability to confer protection against PtERV1 (Figs. 2 and 3) and that modern humans have descended from ancestors who resisted infection. Indeed, we know that there is very little diversity in the human population today in the part of TRIM5 that determines antiviral specificity (6, 16, 17). However, we find that chimpanzee TRIM5 is also capable of restricting PtERV1 and encodes an R332 (Fig. 3), yet chimpanzees contain multiple copies of PtERV1 in their genome and humans do not. Moreover, we find that R332 is monomorphic in the TRIM5 allele in all four subspecies of chimpanzees and in bonobos, which indicates that R332 is evolutionarily conserved through the chimpanzee radiation (in the past 1 to 2 million years). The most parsimonious explanation for the presence of R332 in humans and chimpanzees is that the mutation was fixed in our common ancestor, which presents a paradox because chimpanzee TRIM5 did not protect them against PtERV1. This suggests that TRIM5 alone does not determine retroviral invasion into the germline but that the combination of multiple retroviral restriction factors that are also rapidly evolving, such as the Apobec3 family (18), are necessary to explain ancient transmission events.

Well, no one can say for sure, but I think it seems pretty unlikely that the hominid TRIM5α gene is the result of selection against infection by this particular virus. The chimpanzee and gorilla genomes have more than 100 copies of the viral DNA in their genomes, which means that it was a long-term infectious agent in those lineages, and its genome was often incorporated into its hosts' germlines. It is probable that these viral genes evolved neutrally after being incorporated into the chimpanzee and gorilla genomes: if they were deleterious, they would be gone; if they were adaptive, they would probably be more highly conserved. Neither chimpanzees nor gorillas are known to carry the live virus today, which is therefore presumed to be extinct. If true, that means that both chimpanzees and gorillas lost the virus, probably sometime before 3 million years ago. This loss occurred either because of convergent genetic adaptations in both lineages (I say convergent because they may or may not have involved the same genes), or because of extreme bottlenecks during which the longtime viral parasites were lost by chance.

Now, consider some hypotheses:

Hypothesis 1: The virus was a longtime hominid pathogen, to which TRIM5α was an adaptation. If this were true, then the human genome ought to harbor at least some copies of the viral DNA. It has none. So this hypothesis probably isn't true.

Hypothesis 2: The virus was a severe short-term epidemic in ancient hominids, and we are descended from the only survivors, who happened to have a resistant TRIM5α allele. This is the hypothesis proposed in the quote above. If this were true, then we wouldn't necessarily expect to see copies of the viral genome in human DNA -- the infection and population crash may have happened too fast. But a single epidemic, or even a succession of several epidemics of the virus, would be unlikely to fix a variant allele. After all, neither the Black Death nor smallpox, nor any other historical epidemic has managed such a feat. And viruses with such exceptionally high death tolls do not tend to sustain epidemics through sparse populations like ancient hominids. Indeed, it seems likely that the virus' long survival in chimpanzees and gorillas implies that its hosts survived for a long time with the virus, and dispersed it as they encountered other individuals over time. If the virus let its hominid victims live a long time and thereby spread across low-density hominid populations, then there ought to be at least some copies of it in our genomes. And there aren't any. Also, the TRIM5α protein has a strong signature of positive selection in the human lineage, which means that there have been multiple selected substitutions. Multiple substitutions are very unlikely to have happened simultaneously; it is more likely that they occurred sequentially, taking a long time. So this hypothesis probably isn't true, either.

Hypothesis 3: The virus never infected hominids, who were, after all, allopatric from chimpanzees and gorillas. Instead, some other virus -- or more probably, several viruses -- infecting ancient hominids explain the evolution of the human TRIM5α gene.

I like hypothesis 3 the best; the data don't seem to reject it. Humans are not very susceptible to the PtERV1 virus. Indeed, our own TRIM5α variant, alone or with other genetic adaptations, have have helped to prevent the virus from infecting ancient hominids at all. Or maybe our ancestors never encountered the virus and our TRIM5α is a result of later events.

I should add, from a quick look at Sawyer et al. 2005, that chimpanzees and gorillas share at least one parallel amino acid subsitution in the rapidly-evolving SPRY domain of TRIM5α -- at position 340. The current paper (Kaiser et al. 2007) notes that humans and chimpanzees share a derived amino acid substitution at position 332. That position (332) is important because the biochemical work by Kaiser et al. 2007 and others has shown it is a critical site for human susceptibility to HIV:

For example, the amino acid at position 332 within this patch is a critical determinant of HIV-1 restriction (13). Humans and chimpanzees encode an arginine (R) residue at position 332, whereas the hominoid ancestral residue at this position is a glutamine (Q). Reversing this change (R332Q) had moderate effects on the ability of human TRIM5α to restrict MLV variants (fig. S2). Notably, changing the arginine to the ancestral glutamine abolished the ability of human TRIM5α to efficiently restrict PtERV1 infectivity (Fig. 2B). Unexpectedly, the R332Q mutation had the opposite effect on HIV-1, improving the ability of human TRIM5α to restrict this virus (15) (Fig. 2B). Thus, the R332Q mutation in human TRIM5α reveals a trade-off in TRIM5α's ability to restrict two retroviruses; a mutation that abolished restriction for PtERV1 results in a gain of restriction to other viruses such as HIV-1.

It would be interesting to see what difference the chimpanzee and gorilla alleles at position 340 make; perhaps their TRIM5α protein remains constrained by selection from yet another pathogen?

In any case, during the last few years we have learned a great deal about ancient selection in hominids associated with pathogens. And most of what has come out has been gross changes such as pseudogenization. In this instance, the key information comes from a genomic comparison showing the huge importance of an ancient pathogen in both chimpanzees and gorillas, but not humans.

It is hard to overstate just how glaring these comparisons are -- they are not at all subtle. If most genetic changes during human evolution have been like precision-aimed shots from a sniper rifle, these disease-associated adaptations we've been finding are like blasts from a cannon.

So there is a lot left to discover.

UPDATE (2009/06/19): The original finding that PTERV1 dates to an ancient retroviral infection in chimpanzees and gorillas was found by Yohn et al. (2005). From the abstract:

Phylogenetic analysis of the endogenous retrovirus reveals that the gorilla and chimpanzee elements share a monophyletic origin with a subset of the Old World monkey retroviral elements, but that the average sequence divergence exceeds neutral expectation for a strictly nuclear inherited DNA molecule. Within the chimpanzee, there is a significant integration bias against genes, with only 14 of these insertions mapping within intronic regions. Six out of ten of these genes, for which there are expression data, show significant differences in transcript expression between human and chimpanzee. Our data are consistent with a retroviral infection that bombarded the genomes of chimpanzees and gorillas independently and concurrently, 34 million years ago. We speculate on the potential impact of such recent events on the evolution of humans and great apes.

This paper includes much speculation about the role of retroviruses in promoting bursts of adaptation in ancient chimpanzees and gorillas. That has been a topic of further research, as well.


Kaiser SI, Malik HS, Emerman M. 2007. Restriction of an extinct retrovirus by the human TRIM5α antiviral protein. Science 316:1756-1758. doi:10.1126/science.1140579

Sawyer SL, Wu LI, Emerman M, Malik HS. 2005. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proc Nat Acad Sci USA 102:2832-2837. doi:10.1073/pnas.0409853102

Yohn CT, Jiang Z, McGrath SD, Hayden KE, Khaitovich P, et al. 2005. Lineage-Specific Expansions of Retroviral Insertions within the Genomes of African Great Apes but Not Humans and Orangutans. PLoS Biol 3(4): e110. doi:10.1371/journal.pbio.0030110

John Hawks

John Hawks Twitter

I'm a paleoanthropologist exploring the world of ancient humans and our fossil relatives.

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